Modular cassette synthesis unit

ABSTRACT

Compact modular cassette systems and methods for the synthesis of radiopharmaceutical products are provided, the compact modular cassette system including a modular unit having valve plates, a reaction cassette, a reagent pack, and other seal and connector plates to ensure that reagents can be mixed together inside one or more chambers of the reaction cassette in a timely and efficient manner. When a new chamber for each new reaction or process should be used, a valveless modular system having removable reaction cassettes and the reagent packs may be used. In such a system, the reagent container, the reaction cassette, or both, can be removed from the modular cassette system and discarded after a desired reaction or process has taken place.

This application claims priority to U.S. Patent Application No.61/508,373 filed on Jul. 15, 2011, titled “Modular Cassette SynthesisUnit”; U.S. Provisional Application No. 61/508,294 filed on Jul. 15,2011, titled “Systems, Methods, and Devices for Producing,Manufacturing, and Control of Radiopharmaceuticals”; and U.S. PatentApplication No. 61/508,359 and filed on Jul. 15, 2011, titled “CassetteReaction Vessel Using a Cascade of Valveless Pressure Pumps.” Each ofthe above applications is incorporated by reference herein in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of Invention

Aspects of the present invention relate to methods and systems forreagent interaction in a modular context. More specifically, aspects ofthe present invention relate to methods and systems that effectuate andcontrol reagent interaction through the remote action of pneumaticvalves in a modular context

2. Background

Nuclear medicine is a branch of medical imaging that uses small amountsof radioactive materials to diagnose or treat a variety of diseases,including many types of cancers, heart disease, and other abnormalitieswithin the body. For example, positive emission tomography (PET) is atype of nuclear medicine imaging in which a radiopharmaceutical thatincludes a radionuclide tracer is introduced into the body where iteventually accumulates in an organ or area of the body being examined.The radionuclide gives off energy in the form of POSITRONS, which aredetected by devices, including a PET scanner. In PET,radiopharmaceuticals that incorporate the radionuclide fluorine-18, suchas fluorodeoxyglucose (FDG), 3′-deoxy-3′-[¹⁸F]-pluorothymidine (FLT),[¹⁸F]-fluoromisonidazol (F-MISO), (4-[¹⁸F]-fluorobenzoyl)norbiotinamide(FBB) and PET Perfusion Agents (PPA), are commonly used.

Due to the radioactive nature of radiopharmaceuticals, specialconsideration must be taken in their preparation, handling, anddelivery. Production of fluorine-18 for use in a radiopharmaceutical isoften difficult and/or expensive, requiring specialized equipment, suchas a cyclotron. The production of the radioisotope often occurs at aremote facility by a third party, from which the hospital or labreceives patient doses that are ready to inject. Even if theradioisotope happens to be produced on site, final production of theradiopharmaceuticals used in many diagnostic imaging procedures requiresmanual preparation in a special aseptic environment to ensure a safeinjectable product that is free of environmental contaminants. Inaddition, precise accounting of the radioactive nature of theradionuclide to be used in the radiopharmaceutical for each procedure isrequired, while taking into account that the bulk radionuclide productcontinuously decays over time.

Furthermore, during preparation of radiopharmaceuticals, techniciansmust be shielded from the ionizing radiation of the radionuclide, andthe purity of the radiopharmaceutical must be ensured by filteringand/or avoiding contamination through contact with particles in the air,on a surface, and/or when mixing with a diluting liquid, for example. Inaddition, because of the short half-life of the radionuclide, theefficient scheduling of patients, for example, along with a safe andefficient preparation of the radiopharmaceutical by technicians iscritical to avoid wasting the prepared bulk product of the radionuclide.

Shielded containment systems for use in combining cyclotron-producedradionuclides with non-radionuclide components to produceradiopharmaceuticals have been developed. There are, however, manydrawbacks of these systems. In particular, typically only oneradiopharmaceutical may be produced in a production run. After a run,various radionuclide raw material components and physical systemcomponents must be replaced or decontaminated, which can greatly delaythe production process and/or make the process much less efficient.Further, many aspects of production of radiopharmaceuticals in suchrelated art systems are not automated and/or may require time-consumingand/or awkwardly controllable hand production steps. In addition, theradioactivity and/or quantities of the raw radionuclide and/or theproduced radiopharmaceutical may be inaccurate and/or difficult todetermine precisely. Necessary quality control to be performed on theoutput radiopharmaceutical products may be time-consuming, inaccurate,and/or require high levels of worker input/skill, further hamperingproduction and/or timely delivery of the produced radiopharmaceuticals.

In addition, to carry out a process in which chemical reactions betweena variety of reagents are to take place, such as in the production ofradiopharmaceuticals, a large and complex setup is sometimes needed tochannel liquids, reagents and/or compounds towards a reactor vessel.Channeling various ingredients towards the reactor vessel generallyinvolves the use of tubing, threaded connectors, valving and the like,which are often a source of fluid losses due to fluid being retained ortrapped therein. The uncertainty and un-repeatability of such losses cancreate errors in determining the respective amounts of ingredientsnecessary to complete a desired reaction process with a desired specificyield. Moreover, some ingredients or reagents may have a short shelflife and may have to be used very quickly after manufacture or afterexposure to the environment, which further increases the need forcomplex reaction vessels.

Accordingly, there is a need in the art for systems and methods thatprovide for chemical and/or physical interactions between a plurality ofreagents and ingredients, while reducing or eliminating the need forexcessive connections, tubing, and the like, particularly for thesynthesis of chemical compounds such as, for example,radiopharmaceutical products, that are typically used in smallquantities and that utilize reagents having a short shelf life. Forexample, the radioactive input may be a radioactive isotope typicallyproduced in a cyclotron. There is a further need in the art for methodsand systems that provide for chemical and/or physical interactionsbetween a plurality of reagents and ingredients, while ensuring thatsubsequent reactions are not contaminated by remnants from previousreactions by providing, for example, one or more disposable reactionmodules. There is a further need in the art for methods and systems inwhich one or more reaction modules may be removably connected to oneanother, as such methods and systems may be useful in providing theability to quickly and efficiently dispose a plurality of ingredientsand/or reagents in contact with each other in a reaction vessel orchamber. There is a further need in the art for systems and methods thatprovide for chemical and/or physical interactions between a plurality ofreagents and ingredients when the reagents have a relatively shortlifetime and must be mixed within a short period of time after beingmanufactured or exposed to the environment.

SUMMARY

In light of the above-described problems and unmet needs, a compactmodular cassette system for the synthesis of radiopharmaceuticalproducts may be provided, the compact modular cassette system includinga modular unit having valve plates, a reaction cassette, a reagent pack,and other seal and connector plates, to ensure that reagents can bemixed together inside one or more chambers of the reaction cassette in atimely and efficient manner. According to various aspects of the presentinvention, when it is preferable to use a new chamber for each newreaction or process, a modular system where both the reaction cassetteand the reagent pack are removable may be helpful, where either thereagent container, the reaction cassette, or both, can be removed fromthe modular cassette system and discarded after a desired reaction orprocess has taken place and, for example, the product of the reactionhas been collected or further treated in a subsequent process.

According to various aspects, the physical connection between a reagentpack and the reaction cassette may be provided via one or morecorresponding channels etched, molded or machined in at least one of thereagent pack and the reaction cassette. In addition, reagent transferbetween a reagent pack and a chamber inside the reaction cassette may becontrolled by a module located remotely from both the reagent pack andthe reaction cassette, which remains part of the overall modular system.According to additional aspects of the current invention, a broad sideor broad face of the reaction cassette may be coupled to a correspondingbroad side of the reagent pack or any other module that is part of theoverall modular cassette system in order to allow for fluidicconnections at various locations between neighboring cassettes, packsand other modules. In addition, e.g., radiation sensors and/or otherheating elements may also be coupled to neighboring modules, cassettesor reagent packs. For example, the modular unit may include a number ofpower and fluid supply devices that are to remain stationary, andaccordingly, the removable reaction cassette may be placed at a frontend of the overall modular unit to facilitate operator interaction and,for example, to facilitate removal of the cassette to a disposalcontainer. Furthermore, the modular unit may be coupled to the cassetteso as to be located behind the cassette, which increases convenience ofuse of the modular unit when the modular unit includes communicationlines coupling the cassette to supply lines located at a back portion ofthe modular unit.

The module/cassette structure may also allow for an automatic ejectionof the cassette. This may be advantageous in reducing operator exposureto the cassette and the hazardous radioactivity within waste dropletsremaining within the cassette. The mini cell shielding structure mayallow for the ejected cassettes to be guided to a shielded wastecollection container. Further, future systems, with further development,may automatically install a fresh replacement cassette.

Additional advantages and novel features of these aspects of theinvention will be set forth in part in the description that follows, andin part will become more apparent to those skilled in the art uponexamination of the following or upon learning by practice of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

Various example aspects of the systems and methods will be described indetail, with reference to the following figures, wherein:

FIG. 1 shows a system for radiopharmaceutical preparation according toan aspect of the invention;

FIGS. 2A-2C show perspective views of a multi-synthesis unit accordingto an aspect of the invention;

FIGS. 3A-3C show perspective views of a synthesis module according to anaspect of the invention;

FIG. 4 is a perspective view of a modular cassette system, according tovarious aspects of the current invention;

FIG. 5 is a perspective view of a synthesis module, according to variousaspects of the current invention;

FIGS. 6-7 are perspective views of components of a modular cassettesystem, according to various aspects of the current invention;

FIG. 8 illustrates a principle of fluid transfer according to variousaspects of the current invention;

FIG. 9 presents an example system diagram of various hardware componentsand other features, for use in accordance with an aspect of the presentinvention;

FIG. 10 is a block diagram of various example system components, inaccordance with an aspect of the present invention; and

FIG. 11 illustrates a flow diagram for performing a synthesis method inaccordance with an aspect of the present invention.

DETAILED DESCRIPTION OF PREFERRED ASPECTS

These and other features and advantages of this invention are describedin, or are apparent from, the following detailed description of variousexample aspects.

FIG. 1 shows a system for radiopharmaceutical preparation according toan aspect of the invention. The system 50 may include a shieldedcontainer, such as a mini-cell 52. The mini-cell 52 may includecompartments 54, 56, and 58. Compartments 54 and 56 may each house aframework for mounting specific units, such as multi-synthesis units 60.For example, a multi-synthesis unit 60 may be about 26-30 inches wide,18-22 inches tall, and 18-24 inches deep. A multi-synthesis unit 60 maybe placed on a sliding track, for example, within a compartment so thatthe multi-synthesis unit 60 can easily be accessed for service orreplacement of the modules or their components.

Each multi-synthesis unit 60 may hold any number of modules as can beaccommodated, while maintaining the overall compactness of the system50. In the example shown in FIG. 1, the multi-synthesis units 60 mayeach incorporate up to six modules. For example, the modules mayinclude, but are not limited to, accessory modules 62 and synthesismodules 64. The components of the modules 62 or 64 may be housed in acontainer that allows the modules to be removed easily from amulti-synthesis unit 60. A radiopharmaceutical material may be preparedin a synthesis module 64 with reagents provided from the reagent pack.An additional compartment 58 may be used to store waste products of theradiopharmaceuticals synthesis process of the system 50, for example.

FIG. 2A is a perspective view of a six-module multi-synthesis unit,similar to the multi-synthesis unit 60 discussed in FIG. 1, according toan aspect of the invention. For example, the unit 60 may be sized to fitinto a reduced mini-cell volume, and positioned on slides so that it maybe pulled forward in, e.g., the mini-cell 52, for service. Further,individual modules 62 or 64 may be pulled forward in the multi-synthesisunit 60 for service or replacement. According to various aspects, quickdisconnects and hands-free connections between the modules and amulti-synthesis backplane/bus system (not shown) may be implemented tofacilitate rapid module replacement. For example, as shown in FIGS. 2Band 2C, the backplane/bus approach may allow individual modules to slideinto the system and through “quick disconnects” tie into utilities toinclude power, gasses, solvents, control connections and the like. Theoverall electronics and control package may tie in to this bus and allowthe control to be located remotely and shielded away from the sources ofradioactivity, which traditionally has created reliability issues. Thisis due to the failure of electronic components exposed to high levels ofradioactivity in traditionally packaged synthesis units combiningelectronics (controls) and electromechanical components. According tovarious aspects of the subject invention, package of controls andelectronics may be mounted in separate electrical box outside theshielded cell, and the package may be shared among a group of synthesisunits (e.g., 6-12 synthesis units). In addition, according to variousaspects, a cable management scheme may permit the entire multi-synthesisunit 60 to be pulled forward in the mini-cell for service withoutdisconnecting fluid, gas, and electrical lines from the mini-cell.

FIGS. 3A-3C show a number of perspective views of a synthesis module,similar to the synthesis module 64 in FIG. 1, according to an aspect ofthe invention. More specifically, each of the synthesis modules 64 maybe configured to include, among other things, a group of radiationdetectors 66, fixed air/vacuum connections 68, and floating luerconnections (not shown).

FIG. 4 is a perspective view of a valveless modular reaction system 100,according to various aspects of the current invention. In FIG. 2, thesystem 100 may include a reagent pack 110, a gasket 120 between thereagent pack 110 and a reaction cassette 130. According to variousaspects, both the reagent pack 110 and the reaction cassette 130 may beconnected to a control interface plate 150 located, e.g., at a backportion of the system 100. In FIG. 4, a membrane 140 is provided betweenthe control interface plate 150 and the reaction cassette 130, while thegasket 120 is provided between the reagent pack 110 and the reactioncassette 130. According to various aspects, the gasket 120 and themembrane 140 may provide, e.g., fluid insulation such as water tightnessof the connection between the reagent pack 110 and the reaction cassette130, and between the reaction cassette 130 and the interface plate 150,respectively. Additionally, the gasket 120 and membrane 140 may beindividually used to bond two neighboring cassettes or modules together.The gasket 120 may alternately be comprised of a collection of o-ringsinstead of a continuous sheet. According to various aspects, the system100 may be used for the synthesis of chemical compounds such as, forexample, radiopharmaceutical products, that are typically used in smallquantities and that utilize reagents having a short shelf life.According to various aspects, a reagent cover 102 may be provided tocover and protect the reagent pack 110 from outside environmentalfactors such as heat, humidity and/or impact.

According to various aspects of the current invention, the cassette 130may include one or ore chambers 180 in which a reaction such as, forexample, a synthesis reaction, can take place. The reaction may takeplace in one or more chamber 180 after reagents included in the reagentpack 110 have been transferred into the chamber 180 to start thereaction. Because the overall system 100 is modular and the reagent pack110 is a single unit of the overall modular system 100, the reagent pack110 can be removed independently of the remaining parts or units of thesystem 100 such as, e.g., the cassette 130, and can be replaced witheither another reagent pack having a larger quantity of reagent and/or adifferent reagent. The reagent pack 110 may contain, for example,specific reagents needed for the processing or synthesis of a specificproduct.

According to various aspects of the current invention, the reagent pack110 may be connected to the cassette 130 via one or more supply channels(see, e.g., 320 in FIG. 6) that are constituted by correspondingchannels etched or otherwise formed within either or both the cassette130 and the reagent pack 110 and that are connected to each other viacorresponding holes in the gasket 120. Accordingly, a reagent can betransferred from the reagent pack 110 to the cassette 130 through thegasket 120 without having to use a transfer line or other outsidetransfer device or valve. A more detailed discussion of the connectionbetween the reagent pack 110 and the cassette 130 is provided below inconnection with FIG. 8 below. The gasket 120 may be snugly placedbetween the reagent pack 110 and the cassette 130 to provide insulationand, for example, avoid reagent leakage from the reagent pack 110 and/orfrom the cassette 130 while allowing an efficient communication betweenthe reagent pack 110 and the cassette 130 to provide for complete, fast,and efficient fluid and/or reagent transfer. For example, when reagentshave a short shelf life and must be used within a short period of timeafter being manufactured or after being exposed to the environment, thereagent pack 110 may be stored separately, and inserted into the system100 in fluid communication with the cassette 130 immediately or a shorttime prior to use, as needed.

According to various aspects of the current invention, the cassette 130may be coupled to the planar-shaped interface plate 150 via the membrane140 provided therebetween. According to various aspects of the currentinvention, the interface plate 150 may be connected to the cassette 130via one or more supply channels (not shown) that are constituted bycorresponding channels etched or otherwise formed within either or boththe cassette 130 and the interface plate 150 and that connect to eachother via corresponding holes in the gasket 140. The gasket 140 may besnugly placed between the interface plate 150 and the cassette 130 toprovide insulation and, for example, avoid reagent leakage from theinterface plate 150 and/or from the cassette 130 while allowingcommunication between the interface plate 150 and the cassette 130 toprovide for complete, fast, and efficient fluid and/or reagent transfer.According to various aspects, the interface plate 150 may also be indirect fluid communication with the reagent pack 110 via one or morechannels that may be formed through the interface plate 150, the gaskets140 and 120, and/or the cassette 130, but where the channels do notcommunicate with any chamber 180 of the reaction cassette 130.Accordingly, the reagent in the reagent pack 110 may be directlycontrolled via the interface plate 150. The interface plate 150 mayinclude a plurality of ports 160, located on an opposite surface of theinterface plate 150 to the surface that is in contact with the gasket140, the plurality of ports 160 being used for gas, vacuum and/or fluidto be pumped in, or out of, one or more chambers 180 of the cassette 130and/or the reagent pack 110.

According to various aspects, the ports 160 may be used to flow gas suchas, for example, pressurized gas, into one or more of the supplychannels of the reagent pack 110, or of the cassette 130, or of both thereagent pack 110 and the cassette 130, also in order to induce orprevent the transfer of fluid between the various units of the system100. According to various aspects, the interface plate 150 may haveports 170 connected to supply or drain lines to allow, for example,supply or drainage of reagent, catalyst, or other needed ingredient. Anexperimental foundation for the operation of the units of the system 100to manipulate vacuum and pressurized gas, or pneumatics, to ensurecomplete and fast transfer of liquid and/or reagents from one unit tothe next such as, for example, from the reagent pack 110 to the cassette130 and/or vice-versa, is described below with reference to FIG. 8.

According to various aspects of the current invention, by manipulatingpneumatics via the ports 160, any reagent or combination of reagents andingredients present in the reagent pack 110 may be completely andrapidly transferred to a chamber 180 of the cassette 130 via one or moreof the supply channels connecting the reagent pack 110 and the cassette130, or between one chamber 180 and another chamber 180, via channelsconnecting the chambers 180 within the cassette 130. Manipulating thepneumatics between the reagent pack 110 and the cassette 130 via theports 160 may include, for example, creating a vacuum in a supplychannel connecting the reagent pack 110 and the cassette 130 to create asuction effect and transfer a reagent present in the reagent pack 110into a given chamber 180 of the cassette 130 as a result of that suctioneffect.

According to various aspects of the current invention, the reagent pack110 and one or more chambers 180 of the cassette 130 may be connected toa module such as the module 250 illustrated in FIG. 5 via the ports 160and one or more channels formed in the cassette 130, in the reagent pack110, in the interface plate 150 and in the gaskets 120 and 140 in orderto allow the flow of gas, such as pressurized gas, and/or vacuum, to thereagent pack 110 or to/from a chamber 180. According to various aspects,in order to ensure a complete transfer of reagent from the reagent pack110 to a chamber 180, a vacuum may be applied to the chamber 180 througha supply channel connecting the chamber 180 to a vacuum/gas source viaone or more of the ports 160 to create a pressure gradient between thechamber 180 and the reagent pack 110, while a flow of pressurized gasmay be provided in the reagent pack 110 through a channel connecting thereagent pack 110 to a source of pressurized gas at one or more of theports 160 of the interface plate 150.

Accordingly, the combined action of pressurized gas urging the reagentin an outward direction from the reagent pack 110 via a channel formedin the reagent pack 110, and the action of the pressure gradient orvacuum created inside the chamber 180 and pulling the reagent into thechamber 180 via a suction effect, may ensure a rapid and completereagent transfer from the reagent pack 110 to the chamber 180. It shouldbe noted that in order to prevent premature transfer of reagent betweenthe reagent pack 110 and the chamber 180 from occurring, the fluidpassages may be pinched off by pneumatic action on the membrane 140,past which the fluid channels are routed. Alternatively, a gas may beprovided from the chamber 180 into the reagent pack 110 to keep thereagent in the reagent pack 110 and to prevent the reagent fromaccidentally discharging outside the reagent pack 110 before anappropriate time. When the transfer of reagent from the reagent pack 110to the chamber 180 is desired, the flow of gas from the chamber 180 maybe discontinued and a pressure gradient, such as a vacuum, may becreated as explained below in greater detail in reference to FIG. 8below.

According to various aspects, when forward flow from the reagent pack110 to the chamber 180 is desired, a vacuum is created in the module byopening a vacuum valve coupled to a port 160 of the interface plate 150.As a result, a pressure gradient is created in the chamber 180. Inaddition, pressurized air may be provided to the reagent pack 110 via aport 160 so as to enter the reagent pack 110 from above the fluid levelin the reagent pack 110 and to urge the reagent through a channelconnecting the reagent pack 110 to the chamber 180 until all the reagenthas been transferred from the reagent pack 110 to the chamber 180.According to various aspects, such a transfer is made possible by thecombined action of the pressure gradient created in the chamber 180 andthe pressurized gas in the reagent pack 110.

According to various aspects, the reagent being transferred from thereagent pack 110 into one or more chambers 180 of the modular cassette130 may be a radioactive input, and the synthesis of a product, such asa radioactive product, may take place in a chamber 180 of the cassette130. For example, the radioactive input may be a radioactive isotopetypically produced in a cyclotron. According to various aspects, boththe cassette 130 and the reagent pack 110 may be disposable. Anadvantage of the valveless system illustrated in FIG. 4 is theelimination of problems related to losses created by fluid or reagentremaining in valves and other tubing typically used to connect a reactorwith a source of reagents.

FIG. 5 is a perspective view of a synthesis module in operation,according to various aspects of the current invention. In FIG. 5, thedisposable reaction cassette 230 and the reagent pack 210 are clampedtogether and held attached to the non-disposable module 250 via theclamping mechanism 270 during use of the system 200. According tovarious aspects, the clamping mechanism 270 also provides the pressureand cohesive strength necessary to create a leak-free fluid connectionbetween the reagent pack 210 and the cassette 230 by aligning respectivechannels formed in each of the reagent pack 210 and the cassette 230, aswell as provide enough pressure and cohesive strength between thereagent pack 210 and the reaction cassette 230 to allow the gaskets 220and 240, respectively provided between the reagent pack 210 and thereaction cassette 230, and between the reaction cassette 230 and themodule 250, to fulfill their function of providing insulation andpreventing leakage of reagent or other ingredients. Accordingly, whenthe clamping mechanism 270 is in action, the respective channels in thereagent pack 210 and in the cassette 230, as well as the open channelsformed in the gaskets 220 and 240, are all aligned so as to create fluidconnections between the cassette 230 and the reagent pack 210, as wellas between a cover 202, the module 250 and each of the reagent pack 210and the cassette 230.

According to various aspects, the removable reagent pack 210 may becovered by a protective cover (not shown) on the surface that is incontact with the gasket 220, the protective cover covering one or morecavities or pockets within the reagent pack where an amount and/or anumber of reagents may be stored, as illustrated in FIGS. 6-7 anddescribed below. Accordingly, if the protective cover is punctured, thereagent present in the cavities or pockets is able to be transferred outof the reagent pack 210. Accordingly, the clamping mechanism 270 in oneaspect of the system 200 also provides activation of the connectionsbetween the various modules by, for example, puncturing the protectivecover that may cover the cavities or pockets in the reagent pack 210 inorder to allow reagent located inside the cavities or pockets to bedelivered to a chamber (not shown) of the cassette 230. The clampingmechanism 270 may also provide sufficient pressure to enable the sealinggaskets to seal the various modules and prevent leakage or outsideimpurities from penetrating the modular reaction system 200. Accordingto various aspects, the clamping mechanism 270 may also provide amechanism to allow for the ejection of the cassette 230 and/or of thereagent pack 210 after use.

According to various aspects of the current invention, in operation, thereagent pack 210, which is initially covered on both surfaces by aprotective layer, and which is illustrated in FIGS. 6-7 and described inmore detail below, is removeably inserted in the system 200. Asdiscussed above, on the surface that is to be in contact with thecassette 230, the reagent pack 210 may have a protective membranecovering the surface of the reagent pack 210 and keeping the reagentinside the reagent pack 210. According to various aspects, the reagentpack 210 may include a plurality of cavities or pockets in which one ormore reagents or ingredients may be stored, where each cavity may havetwo exits, a fluid exit and a vent. After the reagent pack 210 isinserted in the system 200, the module 250, actuated, may urge theclamping mechanism 270 to clamp the various modules of the system 200,such as the reagent pack 210 and the reaction cassette 230, and to allowtubes to pneumatically puncture portions of the membrane covering one ormore pockets in the reagent pack 210 in order to allow the transfer ofreagent stored in the one or ore of the pockets from the reagent pack210 to the cassette 230. When the reagent pack 210 is punctured and thestored reagents or ingredients are exposed to the transfer channelsconnecting the reagent pack 210 and the cassette 230, then transfer ofreagent from the reagent pack 210 to the cassette 230 may be performedby manipulating pneumatics as discussed above with respect to FIG. 4.

FIGS. 6-7 are perspective views of components of a modular cassettesystem, according to various aspects of the current invention. Accordingto FIG. 6, the interface plate 305 includes a plurality of perforatingappendages such as, for example, tubes, 320, that may perforate capsulespresent in a reagent pack and that may include reagent. In someimplementations, the interface plate 305 may be made blunt and tallerthan the sharp tubes 320. These blunt features may allow light manualassembly of the reagent pack against the cassette without breaking theseals into any of the sensitive reagent volumes. Once the system isready for synthesis to begin, the module clamps the reagent pack andcassette tightly to the front of the module, in the process, breakingthrough all of the foil barriers. Once this occurs, one may not beallowed to replace the reagent pack, but need to go forward through theprocess or abort it and start over. According to FIG. 7, the reagentpack 310 may include individual phials, vials, pods, or capsules 315 inwhich an amount of reagent may be stored. Accordingly, on the surface ofthe reagent pack 310 that is to be in contact with the cassette 330, theindividual capsules 315 in the reagent pack 310 store one or morereagents. Once the reagent pack 310 is inserted in the system 300, thetubes 320 present on a surface of interface plate 305 directly facingthe surface of the reagent pack 310, may become actuated by the actionof the clamping system, or by an actuation mechanism, and may punctureone or more of the individual capsules 315 in order to allow thetransfer of reagent stored in the capsules 315 of the reagent pack 310to one or more chambers 380 of the cassette 330. According to variousaspects, once the reagent pack 310 is punctured and the stored reagentsor ingredients are exposed to the transfer channels connecting thereagent pack 310 to the cassette 330, the transfer of reagent from thereagent pack 310 to the cassette 330 may be performed pneumatically asdiscussed above with respect to FIG. 2.

FIG. 6 also illustrates the cassette 330 having a plurality of chambers380, where the chambers 380 are connected to each other via channelsformed within the cassette 330, and where any individual chamber 380 maybe independently used as a reaction vessel. It should be noted that thechannels connecting any two chambers 380 may connect the bottom of thefirst chamber 380 to the top of the second chamber 380 in order topermit the pneumatically activated reagent transfer from the firstchamber 380 to the second chamber 380. With respect to FIG. 7, andaccording to various aspects, the phials or capsules 315 may beconfigured to be individual removable units that can be placed atvarious locations of the reagent pack 310. Accordingly, a reagent pack310 may have one or more reagent capsules 315 that contain reagent andthat can be placed at different locations of the reagent pack 310,according to a given need. For example, specific locations of thecapsules 315 may correspond to a configuration where the reagent presentin the capsule 315 is transferred only to specific chambers 380 of thecassette 330. As such, the system 300 allows for an exhaustive controlof the reaction sites within the cassette 330, and may also allow forseveral reactions to take place independently during a same time periodwithin the same cassette 330.

FIG. 8 illustrates a principle of fluid transfer according to variousaspects of the current invention. FIG. 8 is a schematic illustration ofa plurality of mixing chambers 410, 450 and 490, wherein the cavity ineach chamber may be large enough to allow a two-phase mixture of liquidand vapor, and to establish a fluid level with the vapor located abovethe fluid. According to various aspects, the chambers 410, 450 and 490may be reaction chambers of the reaction cassette 130 and/or of thereagent pack 110 discussed above with respect to FIG. 4, and the fluidtransfer between the chambers of the reaction cassette 130 and/or of thereagent pack 110 may be controlled according to the above-discussedvacuum and pressure as described below.

According to various aspects, each chamber may have one or more entryand exit passages. For example, the chamber 410 may be a reactionchamber having input lines 412 and 414 to input fluids, reagents and/orother solid, liquid, or gaseous ingredients, to be mixed or reactedtogether. According to various aspects, the line 422 may be used toprovide the chamber 410 with a pressurized gas such as, for example, N₂or any combination of gas or gases other than N₂, such one or more inertgas, oxygen or air as long as the gas that does not interact with thefluid composition or ingredients present in the chamber 410 to create anunwanted chemical reaction, by opening a valve at the line 422. A gasreferred to as “inert” in this disclosure may be inert with respect tothe fluid, ingredients or reagents present in the chamber 410, evenwithout being inert with respect to other compositions or othercompounds.

An exemplary purpose of the pressurized gas provided via the line 422 tothe chamber 410 is to apply a downward pressure to the fluid present inthe chamber 410 and urge the fluid out of the chamber 410 to chamber 450via the transfer line 430. The chambers 410, 450 and 490 may beconfigured so as to have an amount of space, or distance, between thevacuum lines 424, 464 and 484 and the free surface of the fluid in orderto prevent splashing or splattering from causing fluid to be ingested bythe vacuum lines and thus to be lost from the process. According tovarious aspects, baffles may be used to prevent the fluid from beingingested in a vacuum line. The additional amount of space above the freesurface of the fluid may also be useful when sparging the fluid toremove any gases dissolved in the fluid.

According to various aspects of the current invention, in order totransfer all of the fluid present in the first chamber 410 to the secondchamber 450, the line 422 may be opened to allow a pressurized inert gasto flow into the chamber 410 and to create a pressure urging the fluiddownward in the chamber 410 and ultimately out of the chamber 410 viathe transfer line 430. In addition, the gas line 462 in the secondchamber 450 may be closed, and the vacuum line 464 in the chamber 450may be opened by opening a vacuum valve located at the line 464. As aresult, a vacuum is created in chamber 450, a suction action of thefluid present in the first chamber 410 may be produced through thetransfer line 430. Accordingly, the combined action of the pushingaction of the pressurized gas flowing in the chamber 410 via the line422 and of the suction action of the vacuum created in the transfer line430 and provided via the chamber 450 results in the entirety of thefluid present in the chamber 410 to be transferred rapidly to thechamber 450. According to various aspects, accidental subsequent fluidtransfer to chamber 490 from chamber 450 may also be prevented bymaintaining a positive pressure inside the chamber 490 and the transferline 470 by, for example, flowing gas via the gas line 482 into thechamber 490 and possibly in the transfer line 470. As a result of theexistence of the positive pressure in chamber 490, no fluid that hasbeen transferred from chamber 410 to chamber 450 can accidentally befurther transferred to chamber 490.

It should be noted that during the transfer process, the pressurized gasline 462 of the chamber 450 may remain closed, and no pressurized gas isprovided to the chamber 450. However, a pressurized gas may be providedto the chamber 450 via the gas line 462 before any fluid transfer fromthe chamber 410 to the chamber 450 in order to keep the fluid in thechamber 410 and avoid accidental transfer of fluid via the line 430before such time when fluid transfer is desired. Accordingly, thepressurized gas is flowed inside chamber 450 via the gas line 462 whilethe vacuum line 464 is closed. Because the only other opening in thechamber 450 is the transfer line 430, the pressurized gas flows throughthe transfer line 430 into the fluid present in the chamber 410. As aresult, gas sparging or bubbling of the fluid may occur at the end ofthe transfer line 430 located at the bottom of the chamber 410, whichmay prevent any amount of fluid from accidentally being transferred fromthe chamber 410 to the chamber 450. Accordingly, accidental fluidtransfer may be avoided, and no fluid is transferred before fluidtransfer from chamber 410 to chamber 450 is desired.

According to various aspects of the current invention, the chamber 450may also have one or more input lines such as input lines 452 and 454,through which additional reagents, or ingredients, may be provided, forexample during a second stage of a manufacturing or reaction process,after or before the fluid has been transferred from chamber 410 intochamber 450. Accordingly, mixing of various additional ingredients withthe fluid transferred from the chamber 410 to the chamber 450 may takeplace inside the chamber 450. According to various aspects of thecurrent invention, a subsequent transfer of the fluid now present inchamber 450 to chamber 490 can be accomplished in a similar process tothe process described above with respect to the transfer of fluidbetween chambers 410 and 450. To transfer the fluid from chamber 450 tochamber 490, gas line 462 is opened to allow flow of a pressurized inertgas into chamber 450 while vacuum line 484 of the chamber 490 is openedto create a suction action. As a result, the fluid present in chamber450 is entirely transferred to the chamber 490 via transfer line 470. Inchamber 490, additional ingredients or reactants may be added to thefluid via input lines 492 and 494.

Accordingly, an additional mixture or reaction of various fluids andchemicals may be performed in the successive chambers 410, 450 and 490during separate successive stages of an overall chemical process, andvarious effluents or fluids may be transferred to one or more of thechambers by manipulating the vacuum lines and pressure lines of thevarious chambers as discussed above, and without having to use wetvalves or pumps in the transfer lines. For example, chemical synthesismay be performed in the various chambers 410, 450 and 490 illustrated inFIG. 8. It should be noted that although only three chambers areillustrated in FIG. 8, there may be as many chambers as needed toeffectuate any required number of reaction steps. According to variousaspects, the three chambers 410, 450 and 490 may be reaction chambers ofthe reaction cassette 130 and/or of the reagent pack 110 discussed withrespect to FIG. 4, and the fluid transfer between the chambers of thereaction cassette 130 and/or of the reagent pack 110 may be controlledaccording to the vacuum and pressure control mechanisms described withrespect to FIG. 8.

According to various aspects of the current invention, the above systemand operation can be controlled and operated via hardware and software,as discussed in greater detail below,

FIG. 9 presents an example system diagram of various hardware componentsand other features, for use in accordance with an aspect of the presentinvention. The present invention may be implemented using hardware,software, or a combination thereof and may be implemented in one or morecomputer systems or other processing systems. In one aspect, theinvention is directed toward one or more computer systems capable ofcarrying out the functionality described herein. An example of such acomputer system 500 is shown in FIG. 9. In some aspects, the computersystem 500 may be configured to communicate with the multi-synthesisbackplane/bus system discussed above in FIG. 2A.

Computer system 500 includes one or more processors, such as processor504. The processor 504 is connected to a communication infrastructure506 (e.g., a communications bus, cross-over bar, or network). Varioussoftware aspects are described in terms of this example computer system.After reading this description, it will become apparent to a personskilled in the relevant art(s) how to implement the invention usingother computer systems and/or architectures.

Computer system 500 can include a display interface 502 that forwardsgraphics, text, and other data from the communication infrastructure 506(or from a frame buffer not shown) for display on a display unit 530.Computer system 500 also includes a main memory 508, preferably randomaccess memory (RAM), and may also include a secondary memory 510. Thesecondary memory 510 may include, for example, a hard disk drive 512and/or a removable storage drive 514, representing a floppy disk drive,a magnetic tape drive, an optical disk drive, etc. The removable storagedrive 514 reads from and/or writes to a removable storage unit 518 in awell-known manner. Removable storage unit 518, represents a floppy disk,magnetic tape, optical disk, etc., which is read by and written toremovable storage drive 514. As will be appreciated, the removablestorage unit 518 includes a computer usable storage medium having storedtherein computer software and/or data.

In alternative aspects, secondary memory 510 may include other similardevices for allowing computer programs or other instructions to beloaded into computer system 500. Such devices may include, for example,a removable storage unit 522 and an interface 520. Examples of such mayinclude a program cartridge and cartridge interface (such as that foundin video game devices), a removable memory chip (such as an erasableprogrammable read only memory (EPROM), or programmable read only memory(PROM)) and associated socket, and other removable storage units 522 andinterfaces 520, which allow software and data to be transferred from theremovable storage unit 522 to computer system 500.

Computer system 500 may also include a communications interface 524.Communications interface 524 allows software and data to be transferredbetween computer system 500 and external devices. Examples ofcommunications interface 524 may include a modem, a network interface(such as an Ethernet card), a communications port, a Personal ComputerMemory Card International Association (PCMCIA) slot and card, etc.Software and data transmitted from, e.g., the multi-synthesisbackplane/bus system discussed above in FIG. 2A and transferred viacommunications interface 524 are in the form of signals 528, which maybe electronic, electromagnetic, optical or other signals capable ofbeing received by communications interface 524. These signals 528 areprovided to communications interface 524 via a communications path(e.g., channel) 526. This path 526 carries signals 528 and may beimplemented using wire or cable, fiber optics, a telephone line, acellular link, a radio frequency (RF) link and/or other communicationschannels. In this document, the terms “computer program medium” and“computer usable medium” are used to refer generally to media such as aremovable storage drive 580, a hard disk installed in hard disk drive570, and signals 528. These computer program products provide softwareto the computer system 500. The invention is directed to such computerprogram products.

Computer programs (also referred to as computer control logic) arestored in main memory 508 and/or secondary memory 510. Computer programsmay also be received via communications interface 524. Such computerprograms, when executed, enable the computer system 500 to perform thefeatures of the present invention, as discussed herein. In particular,the computer programs, when executed, enable the processor 510 toperform the features of the present invention. Accordingly, suchcomputer programs represent controllers of the computer system 500.

In an aspect where the invention is implemented using software, thesoftware may be stored in a computer program product and loaded intocomputer system 500 using removable storage drive 514, hard drive 512,or communications interface 520. The control logic (software), whenexecuted by the processor 504, causes the processor 504 to perform thefunctions of the invention as described herein. In another aspect, theinvention is implemented primarily in hardware using, for example,hardware components, such as application specific integrated circuits(ASICs). Implementation of the hardware state machine so as to performthe functions described herein will be apparent to persons skilled inthe relevant art(s).

In yet another aspect, the invention is implemented using a combinationof both hardware and software.

FIG. 10 is a block diagram of various example system components, inaccordance with an aspect of the present invention. FIG. 10 shows acommunication system 600 usable in accordance with, e.g., themulti-synthesis backplane/bus system discussed above in FIG. 2A,according to an aspect of the present invention. The communicationsystem 600 includes one or more accessors 660, 662 (also referred tointerchangeably herein as one or more “users”) and one or more terminals642, 666. In one aspect, data for use in accordance with the presentinvention is, for example, input and/or accessed by accessors 660, 664via terminals 642, 666, such as personal computers (PCs), minicomputers,mainframe computers, microcomputers, telephonic devices, or wirelessdevices, such as personal digital assistants (“PDAs”) or a hand-heldwireless devices coupled to a server 643, such as a PC, minicomputer,mainframe computer, microcomputer, or other device having a processorand a repository for data and/or connection to a repository for data,via, for example, a network 644, such as the Internet or an intranet,and couplings 645, 646, 664. The couplings 645, 646, 664 include, forexample, wired, wireless, or fiberoptic links. In another aspect, themethod and system of the present invention operate in a stand-aloneenvironment, such as on a single terminal.

FIG. 11 illustrates a flow diagram for performing a synthesis method1100 in a modular system, in accordance with an aspect of the presentinvention. The method includes, among other things, providing 1102 oneor more reaction cassettes, and coupling 1104 one or more reagent packsto the one or more reaction cassettes via one or more couplings. Themethod further includes providing 1106 one or more gaskets betweenadjacent cassettes and/or reagent packs to prevent leakage between theadjacent cassettes and/or reagent packs, wherein the one or morecouplings include channels formed in the one or more cassettes, the oneor more reagent packs and the one or more gaskets, and the channels arein communication with one another.

While this invention has been described in conjunction with the exampleaspects outlined above, various alternatives, modifications, variations,improvements, and/or substantial equivalents, whether known or that areor may be presently unforeseen, may become apparent to those having atleast ordinary skill in the art. Accordingly, the exemplary aspects ofthe invention, as set forth above, are intended to be illustrative, notlimiting. Various changes may be made without departing from the spiritand scope of the invention. Therefore, the invention is intended toembrace all known or later-developed alternatives, modifications,variations, improvements, and/or substantial equivalents.

1. A modular reaction system, comprising: one or more reactioncassettes; one or more reagent packs coupled to the one or more reactioncassettes via one or more couplings; one or more mixing chambers; andone or more gaskets between adjacent cassettes and/or reagent packs, theone or more gaskets being configured to prevent leakage between theadjacent cassettes and/or reagent packs; wherein the one or morecouplings consist of channels formed in the one or more cassettes, theone or more reagent packs and the one or more gaskets, a plurality ofthe channels being in communication with one another to ensure fluidtransfer, and the modular reaction system is configured to be releasablycoupled to a computer-assisted backplane control system.
 2. The modularreaction system of claim 1, wherein fluid transfer between the one ormore cassettes and the one or more reagent packs is pneumaticallycontrolled.
 3. The modular reaction system of claim 1, wherein each ofthe one or more reaction cassettes comprises at least one reactionchamber.
 4. The modular reaction system of claim 1, wherein each of theone or more reagent packs comprises at least one reagent capsule.
 5. Themodular reaction system of claim 1, wherein the channels are integrallyformed in the one or more cassettes, the one or more reagent packs andthe one or more gaskets.
 6. The modular reaction system of claim 1,wherein the channels are configured to ensure fluid communicationbetween the one or more cassettes and the one or more reagent packs. 7.The modular reaction system of claim 1, wherein one or more of thechannels formed in each of the one or more cassettes are incommunication with the at least one reaction chamber.
 8. The modularreaction system of claim 1, wherein one or more of the channels formedin each of the one or more reagent packs are in communication with theat least one reagent capsule.
 9. The modular reaction system of claim 1,wherein the fluid transfer between the one or more cassettes and the oneor more reagent packs is controlled via a control module located outsidethe modular reaction system.
 10. The modular reaction system of claim 1,wherein the one or more reaction cassettes, the one or more reagentpacks and the one or more gaskets are maintained in close proximity soas to prevent leakage via a clamping mechanism.
 11. The modular reactionsystem of claim 1, wherein one or more of the reaction cassettes, thereagent packs and the gaskets are at least one of removable andreplaceable.
 12. The modular reaction system of claim 1, wherein themodular reaction system is slidable relative to the computer-assistedbackplane control system via rails.
 13. The modular reaction system ofclaim 1, wherein the computer-assisted backplane control system controlsa plurality of modular reaction systems and components via a bus. 14.The modular reaction system of claim 13, wherein the modular reactionsystem is configured to share controls and utilities associated with thecomputer-assisted backplane control system with the plurality of modularreaction systems and components.
 15. A synthesis method in a modularsystem, comprising: providing one or more reaction cassettes; couplingone or more reagent packs to the one or more reaction cassettes via oneor more couplings; providing one or more mixing chambers; providing oneor more gaskets between adjacent cassettes and/or reagent packs toprevent leakage between the adjacent cassettes and/or reagent packs; andproviding a computer-assisted backplane control system to control themodule reaction system; wherein the one or more couplings consist ofchannels formed in the one or more cassettes, the one or more reagentpacks and the one or more gaskets, the channels being in communicationwith one another, and the modular reaction system is configured to bereleasably coupled to the computer-assisted backplane control system.16. The method of claim 15, further comprising transferring fluidbetween the one or more reagent packs and the one or more reactioncassettes; wherein the fluid transfer is controlled pneumatically. 17.The method of claim 15, wherein: providing the one or more reactioncassettes comprises providing at east one reaction chamber in each ofthe one or more reaction cassettes; and each one of the one or morereagent packs comprises at least one reagent capsule.
 18. The method ofclaim 15, further comprising integrally forming the channels in the oneor more cassettes, the one or more reagent packs and the one or moregaskets.
 19. The method of claim 17, further comprising configuring thechannels to ensure fluid communication between the one or more cassettesand the one or more reagent packs.
 20. The method of claim 19, whereinconfiguring the channels comprises communicating one or more of thechannels formed in each of the one or more cassettes with the at leastone reaction chamber.
 21. The method of claim 19, wherein configuringthe channels comprises communicating one or more of the channels formedin each of the one or more reagent packs with the at least one reagentcapsule.
 22. The method of claim 16, wherein pneumatically transferringthe fluid between the one or more cassettes and the one or more reagentpacks is performed via a control module located outside the modularsystem.
 23. The method of claim 15, wherein coupling one or more reagentpacks to the one or more reaction cassettes comprises clamping the oneor more reagent packs, the one or more gaskets and the one or morereaction cassettes together via a clamping mechanism.
 24. The method ofclaim 15, wherein one or more of the reaction cassettes, the reagentpacks and the gaskets are at least one of removable and replaceable. 25.The method of claim 15, wherein the one or more of the reactioncassettes are automatically ejected into a shielded waste container tominimize personnel exposure once the one or more of the reactioncassettes are spent.
 26. The method of claim 15, further comprisingrobotically installing at least one replacement cassette.
 27. The methodof claim 15, further comprising providing rails to the modular reactionsystem such that the modular reaction system is slidable relative to thecomputer-assisted backplane control system.
 28. The method of claim 15,further comprising using the computer-assisted backplane control systemto control a plurality of modular reaction systems and components via abus.
 29. The method of claim 28, further comprising configuring themodular reaction system to share controls and utilities associated withthe computer-assisted backplane control system with the plurality ofmodular reaction systems and components.
 30. A computer program productcomprising a computer usable medium having control logic stored thereinfor causing a computer to control pneumatic fluid transfer in a modularreaction system, the system comprising: one or more reaction cassettes;one or more reagent packs coupled to the one or more reaction cassettesvia one or more couplings; one or more mixing chambers; and one or moregaskets between adjacent cassettes and/or reagent packs, the one or moregaskets being configured to prevent leakage between the adjacentcassettes and/or reagent packs; wherein the one or more couplingsconsist of channels formed in the one or more cassettes, the one or morereagent packs and the one or more gaskets, a plurality of the channelsbeing in communication with one another to ensure fluid transfer; thecontrol logic comprising computer readable program code means forcontrolling fluid transfer between the one or more cassettes and the oneor more reagent packs, wherein the fluid transfer is pneumaticallycontrolled, and configuring the modular reaction system to be releasablycoupled to a computer-assisted backplane control system.